Impact of nirmatrelvir/ritonavir on the risk of long COVID in outpatients: a systematic review and meta-analysis.

Abstract

Background: This study systematically synthesized existing evidence to evaluate whether outpatient treatment with nirmatrelvir/ritonavir during the acute phase reduces the incidence of long COVID.

Methods: We conducted a systematic search of Europe PMC, Medline, Scopus, and the Cochrane Library from inception to 15 September 2025. Eligible studies compared COVID-19 outpatients prescribed nirmatrelvir/ritonavir during the acute phase with those who did not receive the drug. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model.

Results: Nineteen studies met inclusion criteria. Overall, nirmatrelvir/ritonavir use during acute infection was associated with a significant reduction in the likelihood of developing post-COVID-19 condition (OR 0.85; 95% CI: 0.80-0.91; p < 0.00001; I² = 99%). Protective effects were consistently observed across multiple clinical domains, including cardiovascular (arrhythmia, ischemic disease, heart failure), pulmonary (dyspnea, COPD), thromboembolic (DVT, PE), neurological (stroke, cognitive impairment, headache), psychiatric (depression), gastrointestinal, metabolic (new-onset diabetes), renal (AKI), and general symptoms (malaise and fatigue). Conversely, no significant differences were noted for cough, asthma, dysautonomia, anxiety, PTSD, sleep disturbances, musculoskeletal pain, or olfactory/gustatory dysfunction.

Conclusions: Early outpatient treatment with nirmatrelvir/ritonavir may mitigate the risk of developing several domains of long COVID, though its benefits are not uniform across all symptom categories.